The research described in this proposal investigates the role of miRNAs and their regulation of a synapse associated RNA binding protein, CPEB, in maintaining synapse-specific facilitation and long term memory. CPEB is well studied for its role in enhancing synaptic facilitation and is interesting for its potential role as a synaptic tag and its priority like properties which could maintain the strength of synapses for years long after the initial stimulus has been removed. However, we lack any understanding of its regulation and the mechanism that give rise to its sustained synapse-specific activity. miRNAs are an emerging class of small non coding RNAs that are important post-transcriptional regulators of gene expression. We have preliminary data to support the idea that miRNAs are key regulators of CPEB. It is my hope, therefore, that in exploring the synapse-specific regulatory effect of miRNAs on CPEB, we gain insight not only into how neurotransmitters locally regulate mlNRAs, but also importantly, provide a mechanism for how synapses transition to, and maintain, translation ally active states. I address these questions using the following specific aims: Aim 1: Which miRNAs directly target and regulate Aplysia CPEB? Aim 2: Which of these miRNAs are regulated by serotonin, and how? Aim 3: Does the serotonin-induced miRNA regulation of CPEB occur locally at synapses and is there a feedback mechanism that might drive persistent synapse-specific activity? Relevance: A deeper understanding of CPEB, its regulation at synapses, and its effect on long term memory will likely give us better insight into amnesias, addiction, and other neurological conditions where the flexibility of neuronal connections is compromised.